Process for making aripiprazole particles

ABSTRACT

A method of preparation of crystalline aripiprazole monohydrate includes the use of solution enhanced dispersion by supercritical fluid. Specifically, water is introduced to a stream of supercritical fluid which is then allowed to mix with a stream including a mixture including aripiprazole and a solvent. The mixing results in the substantially simultaneous dispersion and extraction of the aripiprazole from the mixture by the supercritical fluid.

This application claims priority from U.S. Provisional Application No.60/544,118, filed May 6, 2004, incorporated in its entirety herein byreference.

FIELD OF THE INVENTION

The present invention relates to a process for the preparation ofaripiprazole particles, specifically crystalline aripiprazolemonohydrate. The process includes technology related to solutionenhanced dispersion by supercritical fluid.

BACKGROUND OF THE RELATED TECHNOLOGY

Aripiprazole,7-(4-[4-(2,3-dichloropheny)-1-piperazinyl]-butoxy)-3,4-dihydrocarbostyril or7-(4-[4-(2,3-dichloropheny)-1-piperazinyl]-butoxy)-3,4-dihydro-2(1H)-quinolone,is a drug useful as an antipsychotic treatment, as described in U.S.Pat. Nos. 4,737,416 and 5,006,528. The structure of aripiprazole isshown below.

Several polymorphic forms of aripiprazole have been identified. Theseinclude six anhydrous polymorphic forms, designated types I to VI, twopseudo polymorphs, a monohydrate and a ½ ethanolate. These polymorphicforms have been disclosed, for example, in Patent Publication Nos.US2004058935 and WO 03/026659. Aripiprazole anhydrate may be used forthe formulation of therapeutic treatments, however the hygroscopicnature of these crystals has made them difficult to handle, particularlyto prevent exposure to moisture. Upon exposure to water, the anhydrousforms take up water and are converted to a hydrous form or hydrate. Thehydrates are however less bioavailable and result in a slowerdissolution rate than the anhydrous forms. Recently, WO 03/026659disclosed various polymorphic forms of aripiprazole anhydrate, includingan Anhydrate B form having reduced ygroscopicity, and which was thusmore amenable to pharmaceutical processing and formulation. ThisAnhydrate is prepared via a process in which a hydrous form, Hydrate A,serves as an intermediate. This hydrate is prepared from the milling ofwhat is known as Conventional Hydrate, as is disclosed in WO 03/026659.The Hydrate A is then transformed to Anhydrate B through a heatingprocess.

The Hydrate A, also known herein as aripiprazole monohydrate, thoughdemonstrating usefulness as an intermediate, has a low solubility inwater and thus also presents certain processing challenges. The knownprocess of preparing it from Conventional Hydrate by milling has obviousdrawbacks in reduced processing efficiency and cost. It is thereforedesirable to identify a method of preparing aripiprazole monohydratesuitable for use in the preparation of the anhydrate forms.

Generally, the preparation of particles of pharmaceutical compounds oflow aqueous solubility has been addressed, for example, byco-formulation with polymers or other excipients that act as carriers,fillers and/or modifiers. In such modes of preparation, thepharmaceutical compound and the polymer or excipient are co-precipitatedfrom a solvent system in which both are dissolved. Alternatively, theparticles may be formed using a solution enhanced dispersions (SEDS)system, in which fine particles of a poorly soluble material are coatedwith a solubility-enhancing material, first starting with a suspensionof particles of the pharmaceutical compound in a solution of the coatingmaterial. Such a process is taught in Published PCT Application No. WO96/00610. Using this method, however, the particles must be preparedbeforehand and coated in a separate step.

A method for the preparation of particles of poorly soluble materialsusing supercritical fluids is disclosed in U.S. Pat. No. 5,851,453 toHanna et al. (“Hanna”). Hanna describes an apparatus and method forpreparing particles by solution enhanced dispersion by supercriticalfluid (SEDS). According to Hanna's method, SEDS processing includescontrolling the temperature and pressure of a particle formation vesselinto which a supercritical fluid and a mixture including a substancethat is either in solution or suspension are co-introduced. Thecombination of the supercritical fluid and the substance-containingmixture results in the substantially simultaneous dispersion andextraction of the substance from the mixture by the supercritical fluid.

While Hanna gives examples of solids that may be used with the process,there is no disclosure of what properties a solid must possess to beprepared with the process. Furthermore, Hanna does not describe aprocess for the preparation of a crystalline aripiprazole monohydrate.

U.S. Pat. No. 6,461,642 to Bisrat et al. (“Bisrat”) also describes apreparation for particles using a SEDS technique. However, this processis directed toward the preparation of powders for pulmonaryadministration.

In view of the foregoing discussion and recognition of the problemsassociated with preparation of pharmaceutical compounds in general, andaripiprazole anhydrates in particular, it would seem desirable toprovide a process for the preparation of crystalline aripiprazolemonohydrate from unprocessed aripiprazole that provides particles of asize useful for the preparation of an anhydrate form, or forincorporation into pharmaceutical formulations, for example suspensionsfor intramuscular administration.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation ofcrystalline aripiprazole monohydrate from unprocessed aripiprazolecomprising providing a first mixture comprising a solvent andunprocessed aripiprazole, providing a second mixture comprising asupercritical fluid and optionally, a modifier, introducing water to thesecond mixture, introducing the first mixture to the second mixture in aparticle formation vessel, wherein the contacting of the first mixturewith the second mixture produces crystalline aripiprazole monohydrate,and recovering the crystalline aripiprazole monohydrate. Compared to theconventional process of milling used to prepare Hydrate A, as describedin the art, this process utilizes a solution enhanced dispersion system(SEDS) technology.

As used herein, the term “unprocessed aripiprazole” is meant to includeany of the polymorphic forms of aripiprazole, including any crystallineforms, whether anhydrates or conventional hydrate, or aripiprazole inthe amorphous state, any of which may be present in combination in thestarting material. The term “conventional hydrate” means a hydrated formof aripiprazole formed either during synthesis or by hygroscopicconversion of an anhydrate form, which has not been further processed toyield the monohydrate also known as Hydrate A. The term “contacting,” asused in reference to the process of mixing a first mixture with a secondmixture, means combining the two mixtures to facilitate contact of thefinely divided unprocessed aripiprazole with a supercritical fluid topromote molecular rearrangement and the formation of crystals.

In another embodiment, the invention comprises a process for preparing acrystalline aripiprazole monohydrate from unprocessed aripiprazolecomprising the steps of providing a first mixture comprising n-propanoland unprocessed aripiprazole, providing a second mixture comprisingsupercritical carbon dioxide and optionally, a modifier. Preferably, theprocess includes introducing water to the second mixture at a flow rateof about 0.2 L/min or less, introducing the first mixture, at a flowrate of about 0.4 mL.min⁻¹ or less, and the second mixture at a flowrate of about 0.9 mL/min or greater, into a particle formation vessel toproduce crystalline aripiprazole monohydrate, and recovering thecrystalline aripiprazole monohydrate.

The processes according to these representative embodiments of theinvention incorporate a SEDS technique. Generally, the process ofpreparing the crystalline aripiprazole monohydrate includes combining amixture of a solvent and the unprocessed aripiprazole and a secondmixture including a supercritical fluid and optionally a modifier. Wateris then introduced to the second mixture to saturate or partiallysaturate the supercritical fluid, which in certain embodiments may becarbon dioxide. The first and second mixtures are then contacted in aparticle formation chamber to produce the crystalline aripiprazolemonohydrate. Desirably, the introduction of the first and secondmixtures into the particle formation chamber occurs simultaneously. Uponcontact between the two mixtures, the crystalline aripiprazolemonohydrate is formed and agglomerated into particles which may then berecovered.

A further aspect of the present invention provides a crystallinearipiprazole monohydrate having a particle size range from about 1 μm toabout 75 μm, preferably from about 2 μm to about 25 μm, most preferablyfrom about 2 μm to about 10 μm That is produced by a process thatincludes the steps of first providing a mixture of a solvent and theunprocessed aripiprazole and providing a second mixture including asupercritical fluid and optionally a modifier. Water is then introducedto the second mixture to saturate or partially saturate thesupercritical fluid, which may be carbon dioxide. The first and secondmixtures are then introduced to a particle formation chamber to producethe crystalline aripiprazole monohydrate. Finally, the crystallinearipiprazole monohydrate particles are recovered.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a flow diagram describing a schematic process for preparingcrystalline aripiprazole monohydrate.

FIG. 2 is a flow diagram describing an alternate schematic process forpreparing crystalline aripiprazole monohydrate.

DETAILED DESCRIPTION OF THE INVENTION

The unprocessed aripiprazole for use as a starting material in thepresent invention may be selected from conventional hydrate, anhydrates,amorphous forms and combinations thereof.

An aripiprazole material suitable for use as an unprocessed aripiprazolein the invention may be prepared according to the process described inU.S. Pat. Nos. 5,006,528, 4,734,416 and 4,914,094 and relatedapplications, the entire disclosures of which are herein incorporated byreference. For example, aripiprazole can be prepared by the reaction ofa carbostyril compound with a piperazine compound according to thefollowing general scheme:

where X is halogen, a lower alkanesulfonyloxy group, an arylsulfonyloxygroup, an aralkylsulfonyloxy group, in the presence of an inorganic ororganic basic compound, in an organic solvent or in the absence ofsolvent. Such a reaction is described, for example, in publishedEuropean Patent EP 367141B1, the related disclosure of which is hereinincorporated by reference. An improved process for the preparation ofaripiprazole has also been developed that includes reacting acarbostyril compound with a piperazine compound and/or salt thereof inwater, in the presence of an inorganic basic compound present in anamount of from 0.5 to 10 mol per mol of the carbostyril compound. Such aprocess is described in published Patent Application WO 2004/063162, therelated disclosure of which is also herein incorporated by reference.The product of the synthesis is typically an oily substance which may beisolated, extracted, purified and/or crystallized to provide dry, solidproduct.

As otherwise mentioned herein, in various embodiments the startingmaterial may be an aripiprazole hydrate that includes the materialreferred to herein as a conventional hydrate. This hydrate may bedistinguished from the monohydrate formed according to the practice ofthis invention. Since the latter reaction described above uses water, atleast a portion of the product may include such a hydrous form.Moreover, because of the hygroscopicity of the material produced byeither method, conversion to a hydrous form may be anticipated.

The hydrate starting material can be milled via conventional millingmethods to form a monohydrate characterized, in part, by a grain size ofabout 50 μm or less, preferably about 30 μm or less. Grain size may bedetermined according to the following procedure: 0.1 g of the grains tobe measured were suspended in a 20-ml n-hexane solution of 0.5 g soylecithin, and grain size was measured using a size distribution meter(Microtrack HRA, Microtrack Co.)

Crystalline aripiprazole monohydrate (Hydrate A) can be characterized bycertain ordinarily determined physico-chemical characteristics:

(1) It has an endothermic curve which is substantially the same as thethermogravimetric/differential thermal analysis (heating rate 5° C./min)endothermic curve shown in FIG. 1. Specifically, it is characterized bythe appearance of a small peak at about 71° C. and a gradual endothermicpeak around 60° C. to 120° C.

(2) It has an ¹H-NMR spectrum which has characteristic peaks at1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H),2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt,J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H),6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H),7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

(3) It has a powder x-ray diffraction spectrum which is substantiallythe same as the powder x-ray diffraction spectrum shown in FIG. 3.Specifically, it has characteristic peaks at 2θ=12.6°, 15.4°, 17.3°,18.0°, 18.6°, 22.5° and 24.8°.

(4) It has clear infrared absorption bands at 2951, 2822, 1692, 1577,1447, 1378, 1187, 963 and 784 cm⁻¹ on the IR (KBr) spectrum.

(5) It has a mean grain size of 50 μm or less.

The previously known process for preparing aripiprazole monohydraterequires milling of the conventional hydrate, as described above. Inpreparing the monohydrate according to the process of the invention, afirst mixture is prepared which includes the unprocessed aripiprazoleand at least one organic solvent. Ideally, the aripiprazole dissolves inthe solvent forming a solution. The solvent may be any suitable solventknown in the art. Non-limiting examples of suitable solvents for thefirst mixture include methanol, ethanol, n-propanol (n-PrOH),isopropanol, n-butanol, iso-butanol, sec-butanol, ethyl acetate,acetonitrile, tert-butanol, an aldehyde, acetone, dimethylsulfoxide,tetrahydrofuran (THF), dichloromethane, dimethyl formamide (DMF), andcombinations thereof.

The first mixture may also include water. The water may either be addeddirectly to the first mixture, introduced into a supply line throughwhich the first mixture flows, or added as the first and second mixturesare combined, which may be through the use of a coaxial nozzle orthrough a separate stream that will mix with the streams of the firstand second mixtures at the particle formation vessel.

A second mixture is also prepared which includes a supercritical fluidand optionally a modifier. The modifier may be present in an amount fromabout 0 to about 20% by weight, desirably from about 1% to about 20% ofthe second mixture. The modifier may also be referred to as aco-solvent. In general, a modifier is added to change the intrinsicproperties of the supercritical fluid in or around the critical point.In the present invention, the modifier serves the purpose of aiding theremoval of water. It is important that the modifier or co-solvent beeither completely miscible with, or be at least partially soluble inboth the supercritical fluid and water. Considering that water is almostinsoluble in supercritical carbon dioxide, the presence of the modifierallows excess water to be removed from the system.

A variety of supercritical fluids may be used with the presentinvention. These include carbon dioxide, nitrous oxide, sulfurhexafluoride, xenon, ethylene chlorotrifluoromethane, ethane,trifluoromethane, and combinations thereof. Desirably, the supercriticalfluid includes carbon dioxide.

A variety of solvents may also be used as the modifier or co-solvent.Non-limiting examples include methanol, ethanol, n-propanol (n-PrOH),isopropanol, n-butanol, iso-butanol, sec-butanol, tert-butanol, analdehyde, acetone, dimethylsulfoxide, tetrahydrofuran (THF),dichloromethane, dimethyl formamide (DMF), and combinations thereof.

Prior to the combination of the first and second mixtures, water isintroduced to the second mixture. This may be accomplished by a varietyof methods. These include pumping the water into a supply line throughwhich the second mixture flows, or pumping the second mixture through asaturator vessel comprising water.

Where the water is introduced to the supercritical fluid by feeding itinto the supply line, this is typically accomplished at a low flow rate,for example about 0.4 mL/min or less. Desirably, this occurs prior tothe second mixture passing through heat exchanger coils. This allows thesupercritical fluid and the water to mix fully and homogenize at theelevated temperature before contacting the first mixture. Also, prior tocontact with the first mixture, excess water may collect in a pulsedamper vessel, upstream of the particle formation vessel. This serves tominimize the carry over of water into the final aripiprazole product.

When a saturator vessel is used to introduce the water to the secondmixture, the saturator vessel is connected in-line to the supercriticalfluid supply line. The vessel may be approximately a 500 mL vesselincluding up to about 100 mL of purified water. The vessel may also bepacked with small stainless steel coils to increase the surface area andaid equilibration by enhancing the contact area between the water andthe super critical fluid. The supercritical fluid passes through thevessel to incorporate a small proportion of water at its saturationlevel, i.e., about 1% or less.

The first and second mixtures flow through separate channels prior tomixing. The mixing occurs at the particle formation vessel. Desirably,the mixtures are introduced to the particle formation vesselsimultaneously. At the particle formation vessel, the first and secondmixtures are combined by the use of a specifically designed nozzle. Thismay be a sonic nozzle, with an aperture of approximately 0.2 mm. Withthe sonic nozzle, the second mixture exits the nozzle, into the particleformation vessel as it meets the first mixture which enters the vesselthrough a separate channel. The streams of the first and second mixturesmeet close to the nozzle opening, i.e., approximately 4 mm from thenozzle opening.

A coaxial nozzle, with the outlet end in communication with the particleformation vessel, may also be used. This nozzle will have two or morepassages which terminate adjacent to one another at the outlet end. Atleast one passage will carry the flow of the supercritical fluid mixtureand at least one passage will carry the mixture including thearipiprazole mixture. Typically, the outlet end of the nozzle will havea diameter of approximately 0.2 mm. However, a suitable range is fromabout 0.05 mm to about 2 mm, desirably from about 0.1 mm to about 0.3mm.

After the desired production of aripiprazole, the introduction of waterand the first mixture (containing the aripiprazole) are discontinued.Then additional amounts of the second mixture, including thesupercritical fluid, are allowed to flow through the particle formationvessel. Alternatively, the supercritical fluid alone may be allowed toflow through the vessel. This promotes the removal of excess water thatmay be present in the vessel after particle formation.

The process operating parameters for the present invention, includingthe pressure, temperature, solution concentration and flow rates may bemanipulated to control the size, shape and morphology of the monohydratecrystals. With regard to the flow rate, the first mixture will have aflow rate of about 0.4 mL/min or less and the second mixture will have aflow rate of about 9 mL/min or greater. Desirably, the particle size ofthe crystalline aripiprazole monohydrate will be from about 2 μm toabout 25 μm, more desirably from about 2 μm to about 10 μm.

The features and advantages of the present invention are more fullyshown by the following examples which are provided for purposes ofillustration, and are not to be construed as limiting the invention inany way.

EXAMPLES

Several trial runs were performed using various parameters as shown inTables 1-4. Analysis of each of the samples was performed byDifferential Scanning Calorimetry (DSC) and X-Ray Powder Diffraction(XRPD).

Thermal analyses were carried out using Perkin-Elmer Series 7 ThermalAnalysis Apparatus (Perkin-Elmer, USA). DSC was used extensively todetermine the particular polymorphic form by observing the presence orabsence of a de-hydration peak about 100° C.

DSC revealed changes during the heating of a sample, which involvedevolution or adsorption of energy. A sample (2-10 mg) and a chemicallyinert reference material were placed in sealed, crimped aluminum pansand slowly heated in separate cells under a nitrogen atmosphere. When adifference in temperature between the two sample cells was detected, dueto a physical or chemical transition in the test substance, the coolerof the two samples was heated until the difference was eliminated. Theelectrical energy needed to accomplish this was then plotted againsttemperature. An endothermic change indicated that an enthalpy increasehad occurred, and exothermic change indicated that an enthalpy decreasehad occurred. The transition position and shape of the peak giveinformation on the temperature range in which a transition took placeand the type of phase change that had occurred, respectively. Peakanalysis was carried out using the Perkin-Elmer thermal analysissoftware which controlled all thermal analysis techniques.

For analysis of the trial products, a heating rate of 10° C./min overthe range of 20° C. to 160° C. was generally employed.

X-ray powder diffraction (XRPD) was carried out using a Siemens modelD-5000 diffractometer (Karlsruhe, Germany). Many materials arecrystalline and thus show some external and internal symmetry andregularity. This symmetry (termed crystal structure) can be made visibleby XRPD. When a material is irradiated by monochromatic X-rays, apattern is obtained which is characteristic (a fingerprint) of thatmaterial. Hence specific compounds may be identified.

Test samples of unprocessed aripiprazole were prepared by placing themin a mortar and pestle and grinding to a fine powder. This producedthousands of small crystallites and ensured sample homogeneity. Eachtest sample was placed in a standard sample holder and inserted into thediffractometer. Data were collected between 2° and 40° in a stepwisemode (increasing 0.05° at a count interval of three seconds).Calculations of d-spacings and intensity values were made using theintegrated instrument software on an adjacent PC, and compared toliterature values for sample identification.

Comparative Examples (Runs 1-21) Organic Solvent/Water Combinations

Small volumes of water were added directly into the drug solution, i.e.the first mixture, to maintain a single solution while providingsufficient water vapor within the system to promote hydrate formation.The process parameters and results for the runs that included water withthe aripiprazole mixture are shown in Table 1 and Table 2. Varioustrials were carried out using acetone, DMF, THF and n-propanol as theorganic solvent component, with the primary aim of producing themonohydrate polymorph. These solvents were all completely miscible withwater and capable of removing any excess, unassociated water from thesystem prior to extraction by supercritical carbon dioxide. The level ofaripiprazole solubility was found to differ significantly in thesesolvents, so the effect of the solute-solvent interactions could also beobserved. Generally high CO₂ flows>9 ml min⁻¹ were employed incombination with low solution flows<0.4 ml min⁻¹, to produce rapidsupersaturation and a high degree of dispersive energy. Varioustemperatures and pressures were utilized. The effect of adding up to 10%v/v water directly into acetone solutions, 5% v/v water in DMF solutionsand as high as 25% v/v in THF solutions was investigated. Free flowing,crystalline, white powders were consistently produced in high yields(>75% w/w).

The material produced from the experiments shown in Tables 1 and 2 wasanhydrous, as determined by the absence of a dehydration peak on the DSCtrace and by XRPD, which gave the characteristic anhydrous form N1diffractogram. An example of uniform crystalline particles<10 μm in size(81% yield), was obtained from run 11. The particles produced possesseda flat platelet habit when observed under SEM (scanning electronmicroscopy). The characteristic anhydrous polymorph was confirmed byXRPD.

As noted in runs 17-19 and 21, n-propanol (n-PrOH) had the effect ofsignificantly reducing pressure fluctuations at the nozzle. Thesolubility of aripiprazole in n-PrOH is low, only about 7 mg/ml.Therefore, a highly saturated solution could be produced with a very lowsolution concentration. At such low concentrations, the number ofnucleation sites within the nozzle is low enough to prevent substantialblockages. When processing n-PrOH solutions at 4% to 6.5% w/v, pressurefluctuations were reduced to a more satisfactory level of <35 bar. Theuse of n-PrOH also had a direct effect on particle morphology and size.Water was again incorporated into the solution, in an attempt to producethe monohydrate. At 150 bar and 70° C., processing a 91:9 v/v n-PrOH:H₂Osolution at 4 mg/ml, resulted in the formation of small, uniformparticles of low aspect ration (Table 1-run 18). The flat, well faceted,4-6 sided crystals had a narrow size distribution and volume mediandiameter (VMD) of 4.5 μm. The sample was, however, anhydrous. Anadditional experiment showed that anhydrous material was still producedfrom an n-PrOH solution containing 15% v/v water. The DSC trace of thismaterial (Table 2-run 19) also showed only a single melt peak at 138.9°C.

These preliminary SEDS experiments, the comparative example of runs1-21, the results of which are shown in Tables 1-2, highlighted thedifficulty of obtaining the monohydrate when using the straightforwardapproach of adding small volumes of water directly into the organic/drugsolution. Without wishing to be limited to one theory, a possibleexplanation for this is that the solvent/water and the solvent/water/CO₂interactions are simply stronger than the solute-water interaction.Therefore, free water vapor is not made available within the system,because the organic solvent interacts with the water molecules, whichare then extracted directly into the carbon dioxide along with themodifier. Water cannot associate itself with the weakly interactingsolute molecules and as a result anhydrous crystalline material isformed. TABLE 1 ORGANIC SOLVENT/WATER MIXTURE Soln Soln CO Solvent conc.flow Flow Pressure Temp AP Nozzle Yield VMD Run (v/v) (w/v) (ml/min)(ml/min) (bar) (° C.) (bar) (mm) (%) (μm) 1 Acetone:H₂O   1.0 0.2 9 15050 100 0.2 86 — (95:5)  2 Acetone:H₂O   1.0 0.2 9 150 50 >170 0.2 73 —(95:5)  3 Acetone:H₂O   1.0 0.2 20 150 50 >170 0.2 56 — (95:5)  4Acetone:H₂O   0.7 0.4 20 150 50 >150 0.2 89 6.2 (95:5)  5 DMF:H₂O    3.00.2 9 200 70 60 0.2 93 9.4 (95:5)  6 DMF:H₂O    3.0 0.2 10 200 40 >1500.2 74 — (95:5)  7 DMF:H₂O    3.0 0.2 18 150 50 2 None 83 — (95:5)  8Acetone:H₂O   0.7 0.2 20 150 50 5 None 85 — (95:5)  9 DMF:H₂O    9.0 0.220 200 80 >150 0.75 65 — (95:5)  10 DMF:H₂O    7.0 0.2 20 90 80 50 0.7575 — (95:5)  11 THF:H₂O   3.0 0.2 20 200 40 120 0.2 81 5.5 (95:5)  12THF:H₂O   10.0 0.2 20 200 40 OP None — — (95:5)  13 THF:H₂O   3.0 0.2 20200 40 >150 0.3 — — (95:5)  14 THF:H₂O   3.0 0.2 20 200 40 OP 0.2 85 —(95:5)  15 THF:H₂O   1.0 0.4 20 200 40 >150 0.2 83 9.2 (95:5)  16Acetone:H₂O   0.5 0.2 9 150 60 100 0.1 83 — (90:10)  17 n-PrOH:H₂O    0.4 0.3 18 150 80 8 0.2 78 6.3 (94:6)  18 n-PrOH:H₂O     0.4 0.3 20 15070 5 0.2 57 4.5 (91:9)  19 n-PrOH:H₂O     0.4 0.3 20 150 70 15 0.2 818.5 (85:15)  20 THF:H₂O   1.0 0.2 20 200 60 60 0.2 81 11.0 (75:25)  21n-PrOH:H₂O     0.4 0.3 12 150 70 40 0.2 85 — (90.10)VMD = volume median diameterΔP = change in pressure at nozzle aperture

TABLE 2 ORGANIC SOLVENT-WATER MIXTURE Morphology Run (SEM) DSC/XRPDNotes 1 Non-uniform N1/monohydrate — plates mixture 2 Non-uniformN1/monohydrate — plates mixtures 3 Small anhydrous/N1 Increasing CO₂flow yields plates anhydrous polymorph 2-10 μm 4 Small Anhydrous/N1Increasing CO₂ flow yields plates anhydrous polymorph 2-10 μm 5Non-uniform — — plates 6 Small — Increased pressure build up plates 5-20μm 7 Irregular — Flow through nozzle to plates/bars remove anyfluctuations in pressure 8 Irregular — Flow through nozzle toplates/bars remove any fluctuations in pressure 9 — — Run abandoned.Solution crashing out 10 — — Lumpy product-crystalline acicularparticles produced. 11 Small, very Anhydrous/N1 Very static powderuniform (Large ΔP) plates 2-8 μm 12 — — Flow through nozzle. Solutioncrashing out. 13 — — Repeat of 11 with increased nozzle aperture (StillLarge ΔP) 14 — — Direct repeat of 11. Pumps overpressured 15 Small, —Increased water content aggregate plates 5-10 μm 16 Non-uniform PossiblePoor particles plates hydrate - undetermined 17 Small, anhydrous Narrowsize distribution. uniform Small ΔP plates <10 μm 18 Small, anhydrousTiny ΔP. Very narrow size hexagonal distribution (smallest plates,particles) 3-8 μm in size 19 Irregular anhydrous Anhydrous at 15% water.particles, Larger particle size. rounded and plates 20 Larger moreanhydrous Anhydrous at 25% water. aggregated Large particle size.particles 21 Small anhydrous Reduced CO₂ flow. No wt irregular loss onTGA-anhydrous chunks with material rough surfaces

Comparative Example (Runs 27-28) Water Saturated CO₂

As shown in Tables 3 and 4, runs 27 and 28 both utilized a standardT-piece connected prior to the vessel inlet. Water was fed directly intothe supercritical CO₂ flow at very low flow rates (<0.2 ml.min⁻¹)resulting in the water and CO₂ being mixed just prior to contact withthe organic solution within the SEDS nozzle. The goal was to combine theorganic aripiprazole solution with water saturated CO₂ at the nozzle.Non-uniform particles with rough surfaces were produced in contrast withthe desired well faceted crystalline platelets. The samples, whenanalyzed by XRPD and DSC, were anhydrous.

Inventive Examples (Runs 22-75) Water Added to CO₂

Further experiments were conducted by introducing water into thesupercritical CO₂ modifier port. These results are also shown in Tables3 and 4. Using this methodology water was fed at very low flow rates,into the carbon dioxide at the point within the SEDS process when theCO₂ passes through the heat exchanger coils. This allowed the CO₂ andthe water time to mix fully and homogenize at the elevated temperature,before contacting the organic solution. Excess water not taken up intothe CO₂ was found to collect in the 50 ml pulse damper vessel prior tothe nozzle, minimizing the carry over of water into the product.Attempts to promote the formation of aripiprazole using thisexperimental set-up (runs 22 and 23) were conducted initially using 1%w/v TBF solutions processed at 200 bar and 60° C., with CO₂ flows of 10ml min⁻¹ modified with 0.15 ml.min⁻¹ water. Small, irregular,crystalline plates were produced in high yield, i.e., >95%. XRPDanalysis of sample 22 confirmed that this material was the monohydrate.The DSC traces of both samples produced from THF showed very distinct,broad de-hydration peaks between 110-120° C., which are indicative ofthe monohydrate. Small, highly crystalline monohydrate particles couldtherefore be successfully achieved using this experimental approach.This method was repeated using solutions prepared from n-PrOH to observeif smaller, more uniform crystalline particles of low aspect ratio couldbe produced whilst maintaining the monohydrate form. In run 29, waterwas fed via the modifier port, at 0.2 ml.min⁻¹ into a CO₂ stream of 18ml.min⁻¹ to crystallize aripiprazole from a 6 mg/ml n-PrOH solution at150 bar and 70° C. The monohydrate was successfully produced, determinedby the characteristic DSC trace and XRPD diffractogram. Product yieldwas high, 87% and pressure fluctuations remained below 20 bar.

The effect of introducing water into the carbon dioxide in this way andallowing time to homogenize clearly had the effect of facilitatinghydrate formation from the two solvent/water/CO₂ systems investigated.Adequate water was being made available to allow a stable state ofhydration to exist within the system while carbon dioxide effectivelymaintained its anti-solvent property. Several repeat experiments wereperformed to ensure the repeatability of the process. Runs 44-46, 49-53and 58-59 all utilized the introduction of low flows of water into theCO₂ stream via the modifier port, as shown in Tables 3 and 4. Allproduced aripiprazole in its monohydrate form. Particle morphologyconsistently appeared as well faceted, flat, 4-6 sided platelets.Average particle size varied between 4.7-6.3 μm.

A second option for producing water-saturated CO₂ for the SEDSproduction of aripiprazole monohydrate was investigated in runs 61-65.These results are also shown in Tables 3 and 4. A 500 ml stainless steel“saturator” vessel containing up to 100 ml of purified water wasconnected in-line to the CO₂ supply line. This vessel was packed withsmall stainless steel coils to increase the surface area and so aidequilibration by enhancing the contact area between water and carbondioxide. The CO₂ was pumped through this vessel to incorporate a smallproportion of water at its saturation level, less than 1%, beforemeeting the organic solution within the nozzle. This water-saturated CO₂method was used for runs 61-65. The monohydrate was consistently formed.In run 65, the volume of water required to saturate the CO₂ sufficientlywas only 30 ml. Processing a saturated n-PrOH solution with a CO₂ flowof 20 ml.min⁻¹ at 150 bar and 50° C. resulted in the formation of thin,slightly irregular, crystalline platelets when observed by SEM. It wasclear that the size of the particles produced in this way had increasedslightly and also demonstrated a wider size distribution. The lowestsample VMD was 6.5 μm compared with particles of 4.7 μm produced usingthe modifier port approach.

It was established, however, that this method successfully resulted inthe formation of the monohydrate polymorph. The DSC trace of run 65clearly exhibited a large dehydration peak around 120° C. As a result ofprocessing using fully water-saturated CO₂, it was not possible to drythe crystallized material during the CO₂ only drying stage, and the endof the experiment. This resulted in the recovery of a slightly dampproduct. This material was shown by DSC to remain hydrated, after slowdrying in a desiccator.

The inventive examples of runs 66-75 included the method of using asaturator vessel to introduce water to the supercritical fluid. The 500ml saturator vessel was again connected in-line to the CO₂ remainedsupercritical during the process. The water volume within the saturatorwas varied between 50-150 ml and the CO₂ flow rates were increased by afactor of 5-10 times from those employed in the lab-scale process. SEDS™processing of saturated n-PrOH solutions, using the standard 2-componentnozzle configuration/water saturator, was carried out at 150 bar and 70°C. The CO₂ flow rate and water volume, two parameters that greatlyinfluence the residence time of CO₂ within the water rich saturatorenvironment, were shown to affect the state of aripiprazole hydration.

Run 67, utilizing a very high CO₂ flow of 200 ml.min⁻¹ in combinationwith a low water volume of 50 ml, resulted in the formation of small,highly crystalline platelets. The material was anhydrous by DSC, as onlya single melt peak was observed. The particle size and morphology ofthis sample were equivalent to those of samples produced using themodifier port. Repeating the experiment but reducing the CO₂ flow to 150ml.min⁻¹ and increasing the volume of water in the saturator to 100 ml,increased the water/CO₂ contact time. Run 69 resulted in the formationof hydrated aripiprazole. This was confirmed by the characteristic XRPDdiffractogram. As a result of reduced supersaturation effected by thelower flow rate and increased water content of the supernatural CO₂mixture, particle size was shown to have increased to 8.1 μm VMD.Particle morphology, observed by SEM, was more irregular than theanhydrous sample, consisting of larger crystalline bars and plates up to25 μm in size.

A sonic nozzle method was used in runs 70-75. The major differencebetween this method and the standard 2-component nozzle is that thesolution stream is applied separately through a narrow bore solutionline. The solution and supercritical CO₂ streams then meet outside thenozzle aperture. This approach was employed to observe the effect ofsonic velocity processing conditions on a particle size and morphology.The 500 ml saturator was incorporated into the process, including100-150 ml of purified water. Saturated n-PrOH solutions were processedusing extremely high velocity CO₂ (>200 ml.min⁻¹) with solution flows of1-4 ml.min⁻¹. Pressure/temperature combinations of 100 bar, 50° C. and80 bar, 35° C. were employed as these conditions produced CO₂ densitiessuited to “sonic” processing. Although highly crystalline monohydrateparticles were formed readily using this experimental approach, thesamples displayed a flat, platelet habit of irregular size andmorphology. The sample also demonstrated that the lowest monohydrateparticle size, which could be achieved using this technique, was 7.8 μm.It was clear from the SEM images that the particles were irregular andcovered a wide size distribution.

Both methods of adding the water through the modifier port and the useof the saturator vessel (with the sonic nozzle as well as the twocomponent nozzle) successfully and consistently produced the desiredmonohydrate form. TABLE 3 WATER SATURATED CO₂ Soln Soln CO Solvent conc.flow Flow Pressure Temp AP Nozzle Yield VMD Run (v/v) (w/v) (ml/min)(ml/min) (bar) (° C.) (bar) (mm) (%) (μm) 22 THF 1.0 0.2 10 + 0.15 H₂O200 60 20 0.2 99 — 23 THF 1.0 0.2 10 + 0.15 H₂O 200 60 30 0.2 98 — 24n-PrOH 0.6 0.3 18 150 70 30 0.2 98 6.2 25 n-PrOH 0.6 0.6 18 150 70 250.2 97 51 26 n-PrOH 0.6 1.0 18 150 70 10 0.2 90 — 27 n-PrOH 0.6 0.5 18 +0.2 H₂O 150 70 10 0.2 75 — 28 n-PrOH 0.6 0.5  18 + 0.05 H₂O 150 70 250.2 88 — 29 n-PrOH 0.6 0.3 18 + 0.2 H₂O 150 70 20 0.2 87 — 30 n-PrOH 0.60.3 18 150 70 15 0.2 99 — 31 n-PrOH 0.6 0.4 18 + 0.2 H₂O 150 70 10 0.2 —— 32 n-PrOH 0.6 0.5 9 150 50 35 0.2 68 20.3 33 n-PrOH 0.6 0.75 9 150 505 0.2 75 18.5 34 n-PrOH 0.6 1.0 20 150 70 30 0.2 80 13.6 35 n-PrOH 0.61.0 20 150 70 20 0.2 84 12.3 36 n-PrOH 0.6 0.3 20 150 70 30 0.2 80 4.737 n-PrOH 0.6 3.0 200 150 65 10 0.4 81 7.7 38 n-PrOH 0.6 0.3 20 150 7020 0.2 77 5.9 39 n-PrOH 0.6 0.3 20 150 70 30 0.2 80 10.0 40 n-PrOH 0.60.3 20 150 70 40 0.2 90 7.7 41 n-PrOH 0.65 0.3 18 150 70 20 0.2 95 11.542 n-PrOH 0.6 0.2 18 150 70 65 0.2 90 6.7 43 n-PrOH 0.6 0.3 18 150 70 650.2 25 5.8 44 n-PrOH 0.6 0.3 18 + 0.15 H₂O 150 70 10 0.2 ˜100 4.7 45n-PrOH 0.6 0.3 18 + 0.15 H₂O 150 70 20 0.2 90 5.1 46 n-PrOH 0.6 1.0 18 +0.15 H₂O 150 70 40 0.2 84 8.4 47 n-PrOH 0.6 0.5 20 150 70 20 0.2 89 4.748 n-PrOH 0.6 0.5 20 + 0.15 H₂O 150 70 25 0.2 92 5.7 49 n-PrOH 0.6 0.516 + 0.1 H₂O  150 70 25 0.2 99 6.2 50 n-PrOH 0.6 0.3 18 + 0.15 H₂O 15070 25 0.2 96 6.2 51 n-PrOH 0.6 0.3 18 + 0.15 H₂O 150 70 20 0.2 ˜100 5.852 n-PrOH 0.6 0.3 18 + 0.15 H₂O 150 70 20 0.2 ˜100 — 53 n-PrOH 0.6 0.520 + 0.15 H₂O 150 70 30 0.2 89 — 54 n-PrOH 0.6 0.3 20 150 70 25 0.2 — —55 n-PrOH 0.6 0.3 20 150 70 20 0.2 92 — 56 n-PrOH 0.6 0.3 18 + 0.15 H₂O150 70 12 0.2 89 — 57 n-PrOH 0.6 1.0 100 + 0.75 H₂O  150 67 6 0.4 — — 58n-PrOH 0.6 0.3 18 + 0.15 H₂O 150 70 25 0.2 89 — 59 n-PrOH 0.6 0.3 18 +0.15 H₂O 150 70 25 0.2 68 — 60 n-PrOH 0.6 0.3 18 150 40 30 0.2 72 — 61n-PrOH 0.6 0.3 20 150 70 15 0.2 ˜100 — 62 n-PrOH 0.6 0.3 20 150 70 250.2 ˜100 — 63 n-PrOH 0.6 0.3 20 150 70 20 0.2 ˜100 6.9 64 n-PrOH 0.6 0.320 150 70 15 0.2 ˜100 7.3 65 n-PrOH 0.6 0.3 20 150 50 15 0.2 ˜100 6.5 66n-PrOH 0.6 2.0 100 150 68 20 0.4 83 — 67 n-PrOH 0.6 2.0 200 150 65 350.4 90 6.4 68 n-PrOH 0.6 2.0 100 150 63 70 0.2 77 9.1 69 n-PrOH 0.6 2.0150 150 62 100 0.2 75 8.1 70 n-PrOH:H₂O 0.58 2.0 200 150 62 OP Sonic 798.3 (33:1) 0.2 71 n-PrOH 0.6 2.0 180 80 37 0 Sonic — — 0.2 72 n-PrOH 0.64.0 >200 80 37 0 Sonic 78 11.0 0.2 73 n-PrOH 0.6 1.0 >200 100 48 0 Sonic81 7.8 0.2 74 n-PrOH 0.6 4.0 >200 80 38 0 Sonic 83 13.2 0.2 75 acetone3.0 4.0 >200 100 50 0 Sonic — — 0.2

TABLE 4 WATER-SATURATED CO₂ Morphology Run (SEM) DSC/XRPD Notes 22 Wellfaceted Monohydrate/ Sample was slightly wet, crystalline Monohydratewater introduced via CO₂ particles modifier port 23 Well facetedMonohydrate/ Repeat of 22 crystalline Monohydrate particles 24 Smallwell Monohydrate/ Water contamination in pulse defined Monohydratedamper from previous runs prismatic (CO₂ stream wet) slabs/ plates, <6μm 25 Small well anhydrous/N1 No water contamination defined slabs/plates, <6 μm 26 Small well anhydrous Particle size stays small definedafter large increase in slabs/ solution flow rate plates, <6 μm 27Non-uniform anhydrous/N1 Water via T-piece. Powder particles more dense,different with rough morphology surfaces 28 Non-uniform anhydrous Watervia T-piece. Powder particles more dense, different with roughmorphology surfaces 29 Thin slabs/ Monohydrate/ Water via CO₂ modifier.plates <20 Monohydrate port. TGA = 3% wt loss μm due to water 30 ThinMonohydrate/ CO₂ passed through a wet prismatic Monohydrate pulse damper(PD) to pick slabs/ up water .plates, all <20 μm 31 — Monohydrate Watervia CO₂ modifier port. No pulse damper. Damp product. 32 Largeanhydrous/N1 CO₂ flow reduced to produce irregular larger anhydrousparticles chunks up to 150 μm 33 Large — Solution flow increaseirregular further. Little size chunks up difference. to 150 μm 34 Plates— Repeat of 26 with a 5-30 μm larger 500 ml vessel 35 — anhydrous Kitmodification. 15 ml H₂o in 1^(st) PD. Bypass to dry PD with EtOH mod.500 ml 36 Small uniform anhydrous Kit modification. 10 ml H₂O plates <6μm in 1^(st) PD. Bypass to dry PD without EtOH mod. 500 ml. 37 Smalluniform anhydrous Pilot Plant batch (4.3 g). plates Scale up of trial 37to produce an anhydrous batch. 38 Small anhydrous Kit modification. 15ml H₂O crystalline in 1^(st) PD. Vessel filled, slabs/plates run anddried via 1^(st) PD 2-8 μm only. in size 39 Irregular anhydrous Kitmodification. 15 ml H₂O crystalline in 1^(st) PD. Bypass to dry chunksPD for drying stage. with rough surfaces 40 Irregular Monohydrate Repeatof 30 using original crystalline set-up. Wet 1^(st) pulse damper platesup to 30 μm in size 41 Irregular Monohydrate Kit modification. 15 ml H₂Oflat in 2^(nd) PD. Vessel filled, crystalline run dried via 2^(nd) PDonly plates. Some very large 42 Small well anhydrous/N1 Repeat of 24 toproduce the defined monohydrate prismatic (anhydrate formed) slabs/plates, <6 μm 43 Small well anhydrous/N1 Repeat of 24 and 42 usingdefined a different Kit (anhydrate prismatic formed) slabs/ plates, <6μm 44 Small well Monohydrate/ Water via CO₂ modifier port. definedMonohydrate Pulse damper full of water prismatic at end of run. Dampproduct. slabs/ plates, <6 μm 45 Small well Monohydrate/ Repeat of 44.Sample was defined Monohydrate slightly wet, water prismatic introducedvia CO₂ modifier slabs/ port. plates <6 μm 46 Irregular Monohydrate/Water introduced via CO₂ prismatic Monohydrate modifier port. Increasedslabs/plates, throughput gives larger mostly <10 μm particles. 47Uniform, well anhydrous/N1 Anhydrous conditions faceted employed butmaterial crystalline dried with wet CO₂ particles <6 μm 48 Well facetedanhydrous Water introduced via CO₂ prismatic modifier port, but crystals<10 stopped mid way through μm run-anhydrous? in size 49 Well facetedMonohydrate Water introduced via CO₂ 4-6 sided modifier port for entirecrystals run. mostly <10 μm 50 Well faceted Monohydrate Repeat of runs44 and 45 to 4-6 sided produce a 2 g batch for BMS crystals mostly <10μm 51 Well faceted Monohydrate Repeat to produce a 2 g 4-6 sided batchfor BMS crystals mostly <10 μm 52 Well faceted Monohydrate Repeat toproduce a 2 g 4-6 sided batch for BMS crystals mostly <10 μm 53 —Monohydrate Water introduced via CO₂ modifier port. 500 ml vessel.Monohydrate still produced. 54 — anhydrous Produce anhydrous materialand then pass wet CO₂ over product. Run abandoned due to leak. 55 —anhydrous Anhydrous conditions employed but dried using wet CO₂ via a2^(nd) PD with water. 56 — anhydrous Repeat monohydrate production (52)on a different Kit. Appears not reproducible. 57 — — Pilot Plant. Waterintroduced directly into CO₂ stream. Slushy, wet product on filter. 58 —Monohydrate/ Water introduced via CO₂ Monohydrate modifier port forentire run. Repeat 56. 59 — Monohydrate/ Water introduced via CO₂Monohydrate modifier port for entire run. Repeat 58 but short run. 60 —Monohydrate 20 ml H₂O in PD used as a CO₂ saturator vessel. Reducedtemperature also. 61 Irregular Monohydrate/ 100 ml H₂O in 500 ml flatMonohydrate saturator. Damp material crystalline (yield >100%).particles up to 20 μm in size 62 — anhydrous 50 ml H₂O in 500 mlsaturator. Damp material. Reduced water content = anhydrous product. 63Irregular Monohydrate/ 100 ml H₂O in 500 ml crystalline Monohydratesaturator. Damp material plates (yield >100%). Repeat of 61. up to 30 μmin size 64 Irregular Monohydrate/ 100 ml H₂O in 500 ml crystallineMonohydrate saturator. 50 ml vessel plates after saturator for XS water.up to 30 μm Damp material. in size 65 Irregular Monohydrate/ 30 ml H₂Oin 500 ml crystalline Monohydrate saturator. Slightly reduced platestemperature. Damp material. up to 30 μm in size 66 Very large,Monohydrate/ Pilot Plant-Saturator. irregular, Monohydrate 100 ml H₂O in500 ml crystalline saturator. Damp material plates up to 250 μm. 67 —anhydrous Pilot Plant-Saturator. 50 ml H₂O 500 ml saturator. IncreasedCO₂ flow and raised filter. 68 Irregular Monohydrate/ PilotPlant-Saturator. crystalline Monohydrate 100 ml H₂O in 500 ml platessaturator. Damp material. up to 20 μm in size 69 Irregular Monohydrate/Pilot Plant-Saturator. crystalline Monohydrate 100 ml H₂O in 500 mlplates saturator. Increased up to 20 μm CO₂ flow. Damp. in size 70Irregular Monohydrate Sonic Nozzle-Saturator. crystalline 150 ml H₂O in500 ml plates saturator. Solution up to 30 μm crashing out (OP) in size71 — — Sonic Nozzle-Saturator. 150 ml H₂O in 500 ml saturator. Wetslushy product 72 — Monohydrate/ Sonic Nozzle-Saturator. Monohydrate 100ml H₂O in 500 ml saturator. Raised filter. Damp powder 73 — MonohydrateSonic Nozzle-Saturator. 100 ml H₂O in 500 ml saturator. Raised filter.Damp powder 74 — Monohydrate Sonic Nozzle-Saturator. 100 ml H₂O in 500ml saturator. Raised filter. Damp powder 75 — — Sonic Nozzle-Saturator.100 ml H₂O in 500 ml saturator. Wet slushy product.SEM = Scanning electron microscop

While there have been described what are presently believed to be thepreferred embodiments of the invention, those skilled in the art willrealize that changes and modifications may be made thereto withoutdeparting from the spirit of the invention, and it is intended toinclude all such changes and modifications as fall within the true scopeof the invention.

1. A process for preparing a crystalline aripiprazole monohydrate fromunprocessed aripiprazole comprising the steps of: (a) providing a firstmixture comprising a solvent and unprocessed aripiprazole; (b) providinga second mixture comprising a supercritical fluid and optionally amodifier; (c) introducing water to the second mixture; (d) introducingthe first mixture and the second mixture into a particle formationvessel, wherein the contacting of the first mixture with the secondmixture produces crystalline aripiprazole monohydrate; and (e)recovering the crystalline aripiprazole monohydrate.
 2. The process ofclaim 1, further comprising the step of allowing the water and thesecond mixture to homogenize prior to contact with the first mixture. 3.The process of claim 1, wherein introducing water to the second mixtureis conducted by a process selected from the group consisting of: (a)pumping the water into a supply line through which the second mixtureflows; and (b) pumping the second mixture through a saturator vesselcomprising the water.
 4. The process of claim 3, wherein said saturatorvessel further comprises stainless steel coils.
 5. The process of claim1, wherein the first mixture further comprises water.
 6. The process ofclaim 1, wherein the solvent comprises a substance selected from thegroup consisting of methanol, ethanol, n-propanol, isopropanol,n-butanol, iso-butanol, sec-butanol, ethyl acetate, acetonitrile,tert-butanol, an aldehyde, acetone, dimethylsulfoxide, tetrahydrofuran,dichloromethane, dimethyl formamide, and combinations thereof.
 7. Theprocess of claim 1, wherein the solvent comprises n-propanol.
 8. Theprocess of claim 1, wherein the modifier comprises a substance selectedfrom the group consisting of methanol, ethanol, n-propanol, isopropanol,n-butanol, iso-butanol, sec-butanol, tert-butanol, an aldehyde, acetone,dimethylsulfoxide, tetrahydrofuran, dichloromethane, dimethyl formamide,and combinations thereof.
 9. The process of claim 1, wherein thesupercritical fluid comprises a substance selected from the groupconsisting of carbon dioxide, nitrous oxide, sulfur hexafluoride, xenon,ethylene chlorotrifluoromethane, ethane, trifluoromethane, andcombinations thereof.
 10. The process of claim 1, wherein thesupercritical fluid comprises carbon dioxide.
 11. The process of claim1, further comprising the steps of discontinuing the introducing of thefirst mixture, discontinuing the introducing of water to the secondmixture, and introducing additional amounts of the second mixture to theparticle formation vessel before recovering the crystallinearipiprazole.
 12. The process of claim 1, wherein the modifier comprisesup to about 20% of said second mixture.
 13. The process of claim 1,wherein the modifier comprises from about 1% to about 20% of the secondmixture.
 14. The process of claim 1, wherein the second mixture has aflow rate of about 9 mL/min or greater.
 15. The process of claim 1,wherein the first mixture has a flow rate of about 0.4 mL/min or less.16. The process of claim 3, wherein the water has a flow rate of about0.2 mL/min or less.
 17. The process of claim 1, wherein the crystallinearipiprazole comprises particles of a size range from about 1 μm toabout 75 μm.
 18. The process of claim 1, wherein the crystallinearipiprazole comprises particles of a size range preferably from about 2μm to about 25 μm.
 19. The process of claim 1, wherein the simultaneousintroduction of the first mixture and the second mixture is effectedthrough a coaxial nozzle.
 20. A process for preparing a crystallinearipiprazole monohydrate from unprocessed aripiprazole comprising thesteps of: (a) providing a first mixture comprising n-propanol andunprocessed aripiprazole; (b) providing a second mixture comprisingsupercritical carbon dioxide and optionally a modifier; (c) introducingwater to the second mixture at a flow rate of about 0.2 L/min or less;(d) introducing the first mixture, at a flow rate of about 0.4 mL/min orless, and the second mixture, at a flow rate of about 9 mL/min orgreater, into a particle formation vessel wherein the contacting of thefirst mixture with the second mixture to produce crystallinearipiprazole monohydrate; and (e) recovering the crystallinearipiprazole monohydrate.
 21. A crystalline aripiprazole monohydratecomprising the reaction product of separately formed first and secondmixtures which are introduced into a particle formation vessel, thefirst mixture comprising unprocessed aripiprazole and n-propanol and thesecond mixture comprising supercritical carbon dioxide and optionally amodifier.
 22. A crystalline aripiprazole monohydrate comprising thereaction product of a process comprising the steps of: (a) providing afirst mixture comprising a solvent and unprocessed aripiprazole; (b)providing a second mixture comprising a supercritical fluid andoptionally a modifier; (c) introducing water to the second mixture; (d)introducing the first mixture and the second mixture into a particleformation vessel to produce crystalline aripiprazole monohydrate; and(e) recovering the crystalline aripiprazole monohydrate; wherein thecrystalline aripiprazole monohydrate comprises particles from about 2 μmto about 10 μm.
 23. The reaction product of claim 22, wherein theprocess further comprises the step of allowing the water and the secondmixture to homogenize prior to contact with the first mixture.
 24. Thereaction product of claim 22, wherein introducing water to the secondmixture is conducted by a process selected from the group consisting of:(a) pumping the water into a supply line through which the secondmixture flows; and (b) pumping the second mixture through a saturatorvessel comprising the water.
 25. The reaction product of claim 24,wherein the saturator vessel further comprises stainless steel coils.26. The reaction product of claim 22, wherein the solvent comprises amember selected from the group consisting of a methanol, ethanol,n-propanol, isopropanol, n-butanol, iso-butanol, sec-butanol,tert-butanol, an aldehyde, acetone, dimethylsulfoxide, tetrahydrofuran,dichloromethane, dimethyl formamide, and combinations thereof.
 27. Thereaction product of claim 22, wherein the solvent comprises n-propanol.28. The reaction product of claim 22, wherein the supercritical fluidcomprises carbon dioxide.
 29. The reaction product of claim 22, furthercomprising the steps of discontinuing the introduction of the firstmixture, discontinuing the introduction of water to the second mixture,and introducing additional amounts of said second mixture to theparticle formation vessel prior to the recovery of the crystallinearipiprazole.
 30. The reaction product of claim 22, wherein the secondmixture has a flow rate of about 9 mL/min or greater.
 31. The reactionproduct of claim 22, wherein the first mixture has a flow rate of about0.4 mL/min or less.
 32. The reaction product of claim 24, wherein thewater has a flow rate of about 0.2 mL/min or less.